Osmotic device with delayed activation of drug delivery

ABSTRACT

The present invention is directed to a fluid-imbibing drug delivery device which is useful for the initial delayed delivery of an active agent formulation to a fluid environment of use, the initial delay period to startup or activation being of a predetermined length of time. The delivery of the agent formulation from the dispensing device, once begun, is continued over a predetermined prolonged period of time.

RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.07/819,417, filed on Jan. 10, 1992, now U.S. Pat. No. 5,223,265, issuedJun. 29, 1993.

FIELD OF THE INVENTION

The present invention is related to the delayed delivery of an activeagent. More particularly, it is related to osmotically-activated devicesfor dispensing active agents to a biological environment of usefollowing an initial delay.

BACKGROUND OF THE INVENTION

Osmotic dispensing devices for delivery of therapeutically active agentsare well known in the art. Such devices use an expansion means todeliver an agent to an environment of use over a period of hours, daysor months. The expansion means absorbs liquid, expands, and acts todrive out beneficial agent formulation from the interior of the devicein a controlled, usually constant manner. The osmotic expansion means isused to controllably, usually relatively slowly, and over a period oftime, deliver the agent. Because they become activated as soon as theyare placed in a fluid environment, these devices are not generally usedto delay the initial release of the agent. Where osmotic technology hasbeen used to provide an initial delay, the delay is followed by therapid release, or substantially simultaneous introduction, of all of theagent or all of the dosage form(s) containing the agent into theenvironment of use at one time. See, PCT publication WO 92/13521. Thisis not always an appropriate method of delivery, such as when deliveryof an agent at a constant rate over a prolonged period of time isdesired.

The delay of the initial release of an agent has primarily beenpreviously effected by coating the agent or a formulation containing theagent with a dissolvable or bioerodible coating layer, such as gelatinor an enteric coating, which coating layer dissolves or erodes in theenvironment of use to then make the agent available. Delayed initialrelease has also been provided by dispersing the agent in a dissolvableor erodible matrix. However, such systems are often unreliable andrelease cannot be controlled with great accuracy due to the variabilityand relatively uncontrollable nature of erosion and dissolution.

Therefore, there remains a continuing need for improved methods andsystems for providing a delayed activation and thus a delayed initialdelivery of an active agent to an environment of use that are reliableand that can be programmed to deliver the agent after a particularinterval with increased accuracy.

SUMMARY OF THE INVENTION

The present invention is directed to a fluid-imbibing dispensing devicefor the initially delayed delivery of an active agent to a fluidenvironment of use, followed by continuous delivery of the agent to theenvironment over a prolonged period of time. The delivery device of theinvention is formed of a first housing and a second housing with an openend, the housings being in reversibly sliding telescoping arrangementwith each other, which device maintains its integrity in the fluidenvironment; an active agent delivery chamber within the first housingfor the continuous delivery of an active agent to the environment over aprolonged time period, the delivery chamber including at least oneactive agent formulation containing at least one active agent, an exitmeans for providing communication between the active agent formulationand the environment of use, a first expansion means for dispensing theactive agent formulation through the exit means to the environment, andmeans for allowing passage of fluid into the first expansion means (the"fluid-passage means"); and an expansion chamber within the secondhousing for separating apart the first and second housings of the deviceafter exposure to the environment of use to provide the initial delay,the expansion chamber including a second expansion means and a pushplate.

The invention also is directed to a method for delaying the initialdelivery of an active agent to a fluid environment of use, the methodcomprising placing the dispensing device of the invention into theenvironment of use, allowing fluid to be imbibed through at least aportion of the second housing of the dispensing device for causing thesecond expansion means to expand over time and exert pressure on theslidably connected first and second housings to push apart and separatethe two housings of the device to expose the fluid-passage means of thefirst housing to the environment, and allowing fluid to be imbibedthrough the fluid-passage means for causing the first expansion means toexpand to push the active agent formulation from the delivery device,thereby delivering the active agent into the environment of use.

DESCRIPTION OF THE DRAWINGS

The drawings are not drawn to scale, but are set forth to illustratevarious embodiments of the invention. Like numbers refer to likestructures.

FIG. 1 is a cross-sectional view of one embodiment of the deliverydevice of the present invention, the device being in closed or preparedform prior to placement in the environment of use.

FIG. 2 shows the device of FIG. 1 in operation after placement in theenvironment of use, showing the second expansion means expanded and thefirst and second housings of the device separated to allow activation ofthe first expansion means to begin delivery of the active agentformulation to the environment.

FIG. 3 shows the first housing of the device of FIG. 1 in operationtoward the end of its useful life, with the first expansion meansexpanded and a large portion of the active agent formulation deliveredto the environment.

FIG. 4 is a cross-sectional view of another embodiment of the deliverydevice of the present invention, the device being in closed or preparedform.

FIG. 5 is a cross-sectional view of yet another embodiment of thedelivery device of the present invention, the device being in closed orprepared form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a device which is useful for the initialdelayed delivery of an active agent formulation to a fluid environmentof use, the initial delay period to startup or activation being of apredetermined length of time. The delivery of the agent formulation fromthe dispensing device, once begun, is continued over a predeterminedprolonged period of time. By "prolonged period of time", as used herein,is meant an extended time period such as for about 1 hour up to about 48hours.

The dispensing devices of the invention find use, for example, in humansor other animals. The environment of use is a fluid environment and cancomprise the stomach, the intestinal tract, or a body cavity such as theperitoneum or vagina. A single dispensing device or several dispensingdevices can be administered to a subject during a therapeutic program.

FIG. 1 depicts in cross-sectional view a presently preferred embodimentof the delivery device according to the present invention. The device isshown in closed or prepared form prior to placement in the environmentof use. Dispensing device I comprises a first housing 12 and a secondhousing 14. First housing 12 and second housing 14 are in slidablytelescoping arrangement with each other. First housing 12 surrounds anddefines an active agent delivery chamber 16 and contains a firstexpansion means 20 and an active agent formulation 22, which in apreferred embodiment are separated by a moveable impermeable partitionlayer 24 to maintain the separate identities of the agent formulation 22and the first expansion means 20. First housing 12 also comprises anexit means or passageway 28 which provides communication between theenvironment of use and that part of active agent delivery chamber 16containing active agent formulation 22. Adjacent to first expansionmeans 20, on the side opposite from agent formulation 22, isfluid-passage means 26 for allowing the passage of fluid from theenvironment of use into expansion means 20.

Second housing 14 encompasses an expansion chamber 18 and contains asecond expansion means 30 and a moveable impermeable push layer or pushplate 32, push plate 32 being between second expansion means 30 and theend of first housing 12 that comprises the fluid-passage means 26.

First housing 12 and second housing 14 at their ends are close in sizeand they form a friction fit therebetween. The friction generated issufficient to maintain the two housings together prior to activation ofthe second expansion means 30 but not so great as to keep the twohousings from sliding apart once an expanding driving force is exerted.First housing 12 and second housing 14 can be telescoped completely intoa closed and continuous external walled position. The end of firsthousing 12 is adapted to fit within second housing 14. The bottom edgeof the end of first housing 12 provides a platform or ridge 34. Ridge 34is adapted to receive the driving force of second expansion means 30,via push plate 32, to effect the separation of the two housings.

In operation, dispensing device 1 is placed in the fluid environment ofuse and second expansion means 30 begins to imbibe and absorb fluidthrough second housing 14 from the environment. Second expansion means30 expands, exerting a driving force via push plate 32 against end orridge 34 of first housing 12 to begin to slidably separate first housing12 from second housing 14. At a point in time t_(a), first housing 12and second housing 14 are separated apart from each other by the actionof second expansion means 30, via push plate 32, on first housing ridge34. In such manner, fluid-passage means 26 is then exposed to the fluidenvironment, and first expansion means 20 begins to imbibe fluid throughfluid-passage means 26. As first expansion means 20 imbibes fluid, itexpands and pushes against partition layer 24, and the expanding drivingforce of means 20 is conveyed via partition layer 24 against activeagent formulation 22. Agent formulation 22 is then immediately begun tobe expelled in a controlled and continuous manner from active agentdelivery chamber 16 through exit port 28 into the environment of use.The expansion means 20 continues to expand and deliver active agent fora prolonged period of time, t_(b).

FIG. 2 shows the dispensing device 1 of FIG. I in operation at timet_(a) after separation of the two housings of the device by placement inthe fluid environment. First housing 12 has been separated from secondhousing 14 by the expanding driving force of the second expansion means30, which has expanded in size as a result of imbibing fluid from theenvironment. Fluid-passage means 26 is now exposed to the environment sothat the device 1 is activated to begin to deliver active agent.

FIG. 3 shows first housing 12 and the active agent delivery chamber 16of dispensing device 1 of FIG. 1 in operation toward the end of theprolonged period of time t_(b) after most of the active agent has beendelivered to the environment. First expansion means 20 has expanded insize as a result of imbibing fluid through fluid-passage means 26 topush active agent formulation 22 through exit port 28.

FIG. 4 illustrates another embodiment of the device of the invention. Asillustrated in this figure, dispensing device 2 is similar to dispensingdevice 1 of FIGS. 1 and 2, having a first housing 12 with a ridge 34, asecond housing 14, an active agent delivery chamber 16 surrounded anddefined by first housing 12, an expansion chamber 18 defined by secondhousing 14, first expansion means 20, second expansion means 30, pushplate 32, and exit means 28. In dispensing device 2, the active agentformulation is present as a plurality of active agent dosage forms aslayers or tablets 36, 38, 40 and 42. Although four dosage forms areillustrated, the number is not critical and any number of dosage formsare included under the invention. Optionally, layers of a barriermaterial (not shown) may be placed between the agent dosage forms inalternating arrangement to provide a pulsed delivery over a prolongedperiod of time. The exit means or passageway 28 may optionally be closedby an erodible material 44 such as, for example, microcrystalline wax orgelatin, for protecting the active agent formulation prior to placing inthe environment of use, or there may optionally be present a retainingstructure such as a screen or mesh for retaining the dosage forms withinthe device until they are dispensed into the environment. Alternately, alayer of barrier material (not shown) may be present between the firstactive agent dosage form and the environment of use at the exit means,which barrier layer is pushed out by the action of the activated firstexpansion means. Optionally, a partition layer (not shown), such as thepartition layer 24 of device 1 in FIGS. 1, 2 and 3, may be included indevice 2 between first expansion means 24 and dosage tablet 42.

Because first expansion means 20 operates by the imbibition of externalfluid, the wall of first housing 12 is preferably comprised of animpermeable material in at least that portion of the housing that is incontact with the first expansion means 20, so that the first expansionmeans is not prematurely activated prior to the predetermined time t_(a)of separation of the two housings of the device. When an active agent oran active agent dosage form is sensitive to fluid from an exterior fluidpresent in the environment of use, it is preferred that first housing 12be substantially impermeable in its entirety to the ingress of theexternal fluid to serve as a means for substantially protecting theagent or dosage form as well as the first expansion means.

Because first expansion means 20 operates by the imbibition of externalfluid, fluid-passage means 26 adjacent first expansion means 20 mustallow fluid to pass through for activating the expansion means whilebeing impermeable to the ingredients of the expansion means. This may beaccomplished by the fluid-passage means comprising a microporousmembrane or a screen or be of a composition that is semipermeable, or acombination of these. By "semipermeable" is meant that it is permeableto fluid but impermeable to other ingredients contained in thedispensing device.

FIG. 5 illustrates an embodiment where the fluid-passage means comprisesa screen in combination with a semipermeable membrane. Device 3 of FIG.5 has a first housing 12, a second housing 14, an active agent deliverychamber 16, an expansion chamber 18, a first expansion means 20, activeagent formulation 22, a partition layer 24, a second expansion means 30,a push plate 32 and ridge 34. In device 3, the fluid-passage meanscomprises a screen 46 together with a semipermeable membrane 48. Screen46 in this embodiment is molded or otherwise formed as a continuousportion of first housing 12. The screen 46 has openings or pores of sucha size that components of first expansion means 20 could pass out intothe environment of use, in addition to fluid passing into the expansionmeans. Thus, a semipermeable membrane 48 is positioned between screen 46and first expansion means 20 to maintain the components of firstexpansion means 20 within device 3 while allowing fluid from theenvironment to pass through to means 20 via screen 46. In an optionalembodiment of device 3, the push plate 32 is not present, since thecontinuous nature of the screen portion 46 of the housing 12 with thehousing will, in certain embodiments, provide adequate support for theexpanding driving force of the second expansion means 30. The end offirst housing 12 opposite screen 46 and semipermeable membrane 48 isclosed by a cap 50 having exit means or passageway 28 therethrough forenclosing the active agent delivery chamber 16. Cap 50 may be eithersemipermeable or impermeable, depending on the nature of the activeagent formulation 22. Alternatively, exit means 28 may be of a largesize such as that shown in FIG. 4, and optionally may be closed by anerodible material, by a barrier layer, or by a retaining structure suchas a screen or mesh.

Because second expansion means 30 also operates by the imbibition ofexternal fluid, the wall of second housing 14 in at least a portion thatis adjacent to second expansion means 30 must be semipermeable.

The walls of housings 12 and 14 optionally comprise additionalingredients such as, for example, a plasticizer. Impermeable andsemipermeable compositions suitable for use in housings 12 and 14, aswell as suitable additives, are known in the art, examples of which aredisclosed in U.S. Pat. No. 4,874,388, the entire disclosure of which isincorporated herein by reference.

The delivery device of the present invention is nontoxic, biologicallyinert, nonallergenic and nonirritating to body tissue, and it maintainsits physical and chemical integrity; that is, the device does not erodeor degrade in the environment of use during the dispensing period. It iswithin the scope of the invention that the device be insoluble onlyduring the period of intended use and can thereafter dissolve away inthe environment of use. Thus, a dispenser is here contemplated which isunaffected by its environment, solubility-wise, at the situs of use orwhich, alternatively, is only slightly soluble during the period ofintended use, such that once its active agent content has been removedit will then dissolve or erode away.

The first and second expansion means or expandable driving means 20 and30 are nontoxic, nonallergenic and biologically inert. Expansion means20 and 30 may be the same or they may be different. In one presentlypreferred embodiment, means 20 and/or 30 comprises an osmopolymer. Theosmopolymers interact with water and aqueous biological fluids and swellor expand to an equilibrium state. The osmopolymers exhibit the abilityto swell in fluid and to retain a significant portion of the imbibed andabsorbed fluid within the polymer structure. The expansion means 20and/or 30 in another preferred embodiment comprises an osmagent. Theosmagents are known also as osmotically effective solutes and they arealso known as osmotically effective compounds. The osmagents that can beused for the purpose of this invention include inorganic and organiccompounds that exhibit an osmotic pressure gradient across asemipermeable, i.e. a fluid-permeable, wall. The expansion means 20and/or 30 in yet another preferred embodiment comprises an osmagentdispersed within an osmopolymer. The expansion means can comprise atablet or a layer, or a plurality of tablets or layers, and be placedinto position in the device or it can be pressed into the appropriatewall section. The osmagent or osmopolymer can be in any suitable formsuch as particles, crystals, pellets, granules, and the like, whenpressed into a tablet layer and into the wall section. Osmagents andosmopolymers are known to the art and are described in, for example,U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893, 4,327,725 and 4,612,008.

Partition layer 24 and push plate 32, in a presently preferredembodiment, each comprises a composition that is substantiallyimpermeable to the passage of fluid, and they serve to restrict thepassage of fluid present in the expansion means into other areas of thefirst or second housings. They operate to essentially maintain theintegrity of the active agent formulation 22 or the fluid-passage means26 and the expansion means layers. Additionally, and importantly, pushplate 32 acts to insure that the expanding driving force generated bythe second expansion means 30 is applied directly against first housing12 to effect the separation of the first and second housings. Thus, pushplate 32 must be of sufficient strength, thickness and rigidity totransfer the driving force against first housing 12.

Representative impermeable materials useful as a partition layer 24 orpush plate 32 are known to the art in, for example, U.S. Pat. No.4,874,388.

The term "active agent formulation", as used herein, comprises theactive agent to be delivered, as a liquid, solid, semisolid orthermosensitive composition, generally in a carrier substance and withor without additional inert ingredients. The term may additionallyinclude dosage forms comprising the active agent which are capable ofmaintaining their physical configuration and chemical integrity whilehoused within the dispenser. These include, without limitation, tabletswith or without a density element; matrix tablets; spheres; pellets andelongated tablets; capsules; elementary osmotic pumps, such as thosedescribed in U.S. Pat. No. 3,845,770; mini-osmotic pumps, such as thosedescribed in U.S. Pat. Nos. 3,995,631, 4,034,756 and 4,111,202; andmultichamber osmotic systems referred to as push-pull and push-meltosmotic pumps, such as those described in U.S. Pat. Nos. 4,320,759 and4,449,983; all the above patents of which are incorporated herein byreference.

The pharmaceutically acceptable carrier useful herein may comprise morethan one ingredient, such as, for example, a buffer, a viscosityregulating vehicle, a surfactant, dyes, a permeation enhancer,proteinase inhibitors, or other formulation ingredients and additives,as are known in the art. The carrier may contain more than one activeagent. The active agent formulation can erode or disintegrate and can bein the form of a wax formulation, solid core or tablet, for example. Theformulation can immediately dissolve upon exposure to fluid or it mayerode slowly with or without the presence of excipients for controllingerosion.

The active agent formulation can be designed in a multitude of ways toprovide a specific drug delivery profile. One embodiment may comprise aformulation that contains a biologically acceptable solid surfactantwhich is capable of slow dispersion in the environmental fluid. Inanother embodiment, the formulation may contain a fluid-insoluble waxand a surfactant so that the formulation is susceptable to erosion inthe environment. In still another embodiment, the formulation may beeffervescent and provide drug delivery in a finely dispersed form. Thisis accomplished by the addition of a solid basic compound capable ofevolving carbon dioxide in the presence of an acid in the environment ofuse. Suitable basic compounds are disclosed in U.S. Pat. No. 4,265,874.In a further embodiment, the formulation may include an osmotic agent orsolute, such as those described above with reference to the expansionmeans, so that when the formulation comes into contact with theenvironmental fluid, it immediately dissolves. In yet anotherembodiment, the agent formulation can be comprised of an agent and athermoresponsive composition. In this manner, the formulation wouldexhibit solid-like properties at room temperature of 21° C. and within afew degrees Celsius thereof, and would have a melting point thatapproximates mammalian body temperatures of 37° C. and within a fewdegrees Celsius thereof. The term "thermoresponsive" as used herein in apreferred embodiment denotes the physical-chemical property of an agentcarrier composition to exhibit solid, or solid-like properties attemperatures up to 31° C. and become fluid, semi-solid or viscous whendisturbed by heat at temperatures from 31° C., usually in the range of31° C. to 45° C. Suitable materials useful as active agent carriers andexcipients are known in the art and are disclosed in U.S. Pat. Nos.4,595,583 and 4,874,388, for example.

The terms "active agent" and "drug" are used interchangeably herein andrefer to an agent, drug, compound, composition of matter or mixturethereof which provides some therapeutic, often beneficial, effect. Thisincludes pesticides, herbicides, germicides, biocides, algicides,rodenticides, fungicides, insecticides, antioxidants, plant growthpromoters, plant growth inhibitors, preservatives, antipreservatives,disinfectants, sterilization agents, catalysts, chemical reactants,fermentation agents, foods, food supplements, nutrients, cosmetics,drugs, vitamins, sex sterilants, fertility inhibitors, fertilitypromoters, microorganism attenuators and other agents that benefit theenvironment of use. As used herein, the terms further include anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; avians; domestic household or farmanimals such as cats, dogs, sheep, goats, cattle, horses and pigs;laboratory animals such as mice, rats and guinea pigs; fish; reptiles;zoo and wild animals; and the like. The active drug that can bedelivered includes inorganic and organic compounds, including, withoutlimitation, drugs which act on the peripheral nerves, adrenergicreceptors, cholinergic receptors, the skeletal muscles, thecardiovascular system, smooth muscles, the blood circulatory system,synoptic sites, neuroeffector junctional sites, endocrine and hormonesystems, the immunological system, the reproductive system, the skeletalsystem, autocoid systems, the alimentary and excretory systems, thehistamine system and the central nervous system. Suitable agents may beselected from, for example, proteins, enzymes, hormones,polynucleotides, nucleoproteins, polysaccharides, glycoproteins, M.lipoproteins, polypeptides, steroids, hypnotics and sedatives, psychicenergizers, tranquilizers, anticonvulsants, muscle relaxants,antiparkinson agents, analgesics, antiinflammatories, local anesthetics,muscle contractants, antimicrobials, antimalarials, hormonal agentsincluding contraceptives, sympathomimetrics, polypeptides and proteinscapable of eliciting physiological effects, diuretics, lipid regulatingagents, antiandrogenic agents, antiparasitics, neoplastics,antineoplastics, hypoglycemics, nutritional agents and supplements,growth supplements, fats, ophthalmics, antienteritis agents,electrolytes and diagnostic agents.

Examples of beneficial agents which this invention can be utilized withare prochlorperazine edisylate, ferrous sulfate, aminocaproic acid,mecaxylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, methamphetamine hydrochloride, benzphetamine hydrochloride,isoproteronol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindone, diphenadione erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, dexamethasone and its derivatives such asbetamethasone, triamcinolone, methyltestosterone, 17-β-estradiol,ethinyl estradiol, ethinyl estradiol 3-methyl ether, pednisolone,17-β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, aspirin, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenbufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinopril, enalapril, captopril, ramipril, enalaprilat,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptylin, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, insulin, colchicine, glucagon, thyroid stimulating hormone,parathyroid and pituitary hormones, calcitonin, renin, prolactin,corticotrophin, thyrotropic hoemone, follicle stimulating hormone,chorionic gonadotropin; gonadotropin releasing hormone, bovinesomatotropin, porcine somatropin, oxytocin, vasopressin, prolactin,somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH,interferons, interleukins, growth hormones such as human growth hormone,bovine growth hormone and porcine growth hormone, fertility inhibitorssuch as the prostaglandins, fertility promoters, growth factors, andhuman pancreas hormone releasing factor.

It is to be understood that more than one active agent may beincorporated into the active agent formulation in a device of thisinvention, and that the use of the term "agent" or "drug" in no wayexcludes the use of two or more such agents or drugs.

The agents can be in various forms, such as uncharged molecules,components of molecular complexes or nonirritating, pharmacologicallyacceptable salts. Also, simple derivatives of the agents (such asethers, esters, amides, etc.) which are easily hydrolyzed by body pH,enzymes, etc., can be employed.

The amount of active agent employed in the delivery device will be thatamount necessary to deliver a therapeutically effective amount of theagent to achieve the desired result at the site of delivery. Inpractice, this will vary widely depending upon the particular agent, thesite of delivery, the severity of the condition, and the desiredtherapeutic effect. Thus, it is not practical to define a particularrange for the therapeutically effective amount of active agentincorporated into the device.

As used herein, the terms "therapeutically effective" amount or raterefer to the amount or rate of the active agent needed to effect thedesired therapeutic, often beneficial, result.

The terms "exit means" and "exit passageway", as used herein, comprisemeans and methods suitable for the metered release of the active agentformulation from agent delivery chamber 16 of the delivery device of thepresent invention. The exit means 28 includes at least one passageway,orifice, or the like, through first housing 12 for communicating withagent delivery chamber 16. The expression "at least one passageway"includes aperture, orifice, bore, pore, porous element through which theagent can migrate, hollow fiber, capillary tube, porous overlay, porousinsert, and the like. The expression also includes material that isdischarged, erodes or is leached from the wall of the first housing inthe fluid environment of use to produce at least one passageway in thedelivery device. Representative materials suitable for forming at leastone passageway, or a multiplicity of passageways, include an erodiblepoly(glycolic) acid or poly(lactic) acid member in the wall; agelatinous filament; poly(vinyl alcohol); leachable materials such asfluid-removable pore-forming polysaccharides, salts, or oxides; erodableor dischargable materials such as natural and synthetic waxes; and thelike. The expression includes structural characteristics thatconcentrate stress at a precise point in the wall so that only a smallamount of force will induce breakage in the wall, yielding a passagewaythrough the wall from agent delivery chamber 16 to the outside of thedevice. A passageway or a plurality of passageways can be formed byleaching a material such as sorbitol, lactose and like water-solublesolids from the wall. A passageway or passageways can be formed by thedischarge, as a result of the pressure created by the expandable drivingmeans for example, of a material such as a wax. The exit means orpassageway can have any shape such as round, triangular, square,elliptical, and the like, for assisting in the metered release of activeagent from the delivery device. The delivery device can be constructedwith one or more passageways in spaced-apart relations or more than asingle surface of a dosage form. Passageways and equipment for formingpassageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899;4,063,064; and 4,088,864. Passageways formed by leaching are disclosedin U.S. Pat. Nos. 4,200,098 and 4,285,987.

The total delay time prior to separation of the two housings of thedispensing device and the total delivery time of the active agentformulation can be controlled by a number of means to provide a sharpstart-up of delivery at a particular time with high accuracy. Forexample, the rate of fluid imbibition into each of the expansion means,and thus the rate of expansion of the means, can be controlled by theparticular choice of semipermeable membrane or microporous screen. Therate of expansion of the expansion-means can also be controlled by thechoice of composition of the expansion means. The distance of overlapbetween the telescoping portions of the first and second housings candetermine the period of time required for the two housings to separate.Combinations of such control means may be used. Such control means areknown in the art and can be determined without undue experimentation.

The delivery device of the present invention can be manufactured bystandard manufacturing techniques. For example, in the preparation ofdevices of the present invention, first housing 12 (the vessel) andsecond housing 14 (the cap) may be separately molded or extruded to thedesired shape. Possible semipermeable materials from which the secondhousing 14 may be prepared include, for example, Hytrel® polyesterelastomers (Du Pont), cellulose esters, water flux enhancedethylene-vinyl acetate copolymers, semipermeable membranes made byblending a rigid polymer with water-soluble low molecular weightcompounds, and other semipermeable materials known to the art. ,Impermeable materials from which the first housing 12 may be preparedinclude, for example, polyethylene, polystyrene, ethylene-vinyl acetatecopolymers, Hytrel® polyester elastomers (Du Pont) and other impermeablematerials known to the art. Alternatively, the two portions of a hardgelatin capsule may be coated, one with an impermeable material and theother with a semipermeable material such as cellulose ester-basedpolymer mixtures. In a presently preferred embodiment, the assembleddevice in closed configuration is about the size and dimensions of asize "0" to size "00" hard gelatin capsule. The exit means 28 may beformed during the molding process or may be drilled after the vesselportion has been made.

A "first bilayer osmotic plug" composed of impermeable partition layer24 and first osmotic layer or expansion means 20 is prepared in a shapethat will fit within vessel 12. The two layers are compressed into atablet on a rotary bilayer tablet press.

A "second bilayer osmotic plug" composed of second osmotic layer orexpansion means 30 and impermeable push plate 32 is prepared in a shapethat will fit within cap 14. The osmotic plug is compressed on a bilayerrotary tablet press.

The device can be assembled by first placing a soluble seal or a hardgelatin cap over exit means 28 in vessel 12. Active agent formulation 22is then placed in the vessel at its end opposite the exit means, whichend is initially open; the formulation may be in the form of a liquid,solid, semisolid, powder or shaped tablet or tablets, for example. Thefirst bilayer osmotic plug is then inserted on top of the agentformulation with the partition layer portion of the plug next to theagent fill, taking care that the least possible air gap exists betweenthe agent fill and the first bilayer osmotic plug. Fluid-passage means26 is then placed in vessel 12 in such manner that the final position ofthe passage means 26 is against the expansion means portion of the firstosmotic plug and also is flush with the open end of the vessel. Thefluid-passage means may be fixed into place (by adhesive bonding,ultrasound welding or mechanical fitting, for example). The secondbilayer osmotic plug is placed within the cap 14 and the cap assembly isplaced over the end of the filled vessel 14 so that push plate 32 isadjacent to fluid-passage means 26, to give a device as illustrated inFIG. 1. In an alternative assembly method, the device may be assembledas described above, but without addition of the active agentformulation. After assembly is completed, the device is oriented withthe cap portion downwards and liquid or molten agent formulation isplaced in the vessel portion through orifice 28. After filling, the openorifice may be sealed, if desired.

When the device of the invention has the configuration of FIG. 4, it maybe prepared by molding or extruding a first housing or vessel 12 withtwo initially open ends. The fluid-passage means 26 is fitted flush toone end of the vessel cylinder and fixed within the cylinder (byadhesive bonding, ultrasound welding, or mechanical fitting, forexample). The semipermeable second housing or cap 14 containing thesecond bilayer osmotic tablet (prepared as described above) is thenplaced over the passage means-containing end of the vessel. The firstbilayer osmotic plug (as above) is inserted, expansion means layerfirst, through the other or drug delivery end of the vessel 12 and isplaced flush with the fluid-passage means 26. The remainder of thevessel portion is then filled with active agent, typically in the formof one or more active agent tablets. The active agent tablets mayoptionally be separated by non-active agent-containing layers or tabletsto provide a pulsed delivery of agent to the environment of use. Afterall agent formulation has been placed in the vessel, a cap 44, screen orother covering may be placed over the open end, if desired.

When the device of the invention has the configuration of FIG. 5, it maybe prepared by molding or extruding a first housing or vessel 12 in theshape of a cup where the base of the cup has pores or other openingsformed therein for the passage of fluid. This forms the screen portion46 of the fluid-passage means. A semipermeable membrane 48 is thenplaced within the vessel 12 so that it is adjacent to the cup bottom orscreen 46. The semipermeable second housing or cap 14 containing thesecond bilayer osmotic tablet (prepared as described above) is thenplaced over the screen end of the vessel. The first bilayer osmotic plug(as above) is inserted, expansion means layer first, through the open ordrug delivery end of the vessel 12 and is placed flush with thesemipermeable membrane 48. The remainder of the vessel portion is thenfilled with active agent, typically in the form of one or more activeagent tablets. The active agent tablets may optionally be separated bynon-active agent-containing layers or tablets to provide a pulseddelivery of agent to the environment of use. The active agent mayalternatively be a fluid, solid, semi-solid or thermoresponsivematerial. After all agent formulation has been placed in the vessel, acap 50 is placed over the open end. Exit means 28 may be formed when cap50 is molded or otherwise made, or exit means 28 may be formed later bydrilling, for example. Alternatively, it may be desirable, based on thecontent and/or form of the drug formulation or the intended releaseprofile, to have no cap at all on the device, or to have a cap thatdissolves or erodes after placement in the fluid environment, or toplace a screen or other permeable retaining means over the open end ofthe vessel.

The following examples are illustrative of the present invention. Theyare not to be construed as a limitation of the scope of the invention.Variations and equivalents of these examples will be apparent to oneskilled in the art in light of the present disclosure, the drawings andthe claims herein.

EXAMPLE 1

A delivery device according to the present invention is prepared asfollows.

The first osmotic engine portion of the device is a compressed bilayertablet composed of 200 mg of a polymeric osmotic formulation (firstexpansion means) and a 50 mg wax-based partition layer.

The polymeric osmotic formulation has a composition of 59.5 wt %polyethylene oxide (Polyox® 303, Union Carbine), 29 wt % sodiumchloride, 5 wt % polyacrylic acid (Carbomer® 934P, B.F. Goodrich), 5 wt% hydroxypropylmethylcellulose E-5 (Aqualon) and 1 wt % ferric oxide.During preparation, each of the above components is screened through a40 mesh screen, and the sized components are added to a mixing vessel inthe appropriate porportions. The dry components are mixed thoroughly for10 minutes; then, ethanol is slowly added while mixing until a wet masshas formed. The wet mass is then screened through a 20 mesh screen, andthe wet granules are allowed to air dry for 18 hours. After drying, thegranules are passed once more through a 20 mesh screen. Magnesiumstearate (0.5 wt %) is then added to the granulation and the granulationis mixed thoroughly for 5 min.

The partition layer has a composition of 95 wt % microcrystalline wax(MF-2JH Durawax®, Astor Wax Corp.) and 5 wt % gelatin (Type A, 250-300bloom, Knox Gelatin). During preparation, each component is screenedthrough a 40 mesh screen before being added in the correct weight ratioto a mixing vessel. The dry materials are then mixed thoroughly for 10minutes, after which purified water is slowly added to the mixture whilestirring is continued. After a wet mass has formed, the mixture ispassed through a 20 mesh screen, and the granules are oven-dried at 40°C. for 24 hours. After the granules have dried, they are rescreenedthrough a 20 mesh screen.

The osmotic formulation (200 mg) for the engine and the wax formulation(50 mg) for the partition layer are compressed together in a rotarypress into a cylindrical bilayer tablet with both the osmotic engineface and the partition face of the tablet being flat. Tabletting isconducted to produce a clean, distinct interface between the two layers.

The second osmotic engine portion of the device is a compressed bilayertablet composed of a 50 mg wax-based push plate and 150 mg of apolymeric osmotic formulation (second expansion means). The compositionof the second osmotic formulation is the same as or can be differentfrom that for the first osmotic formulation above, and the compositionof the push plate is the same as that for the partition layer above. Theosmotic formulation (150 mg) and the wax push plate formulation (50 mg)are compressed in a rotary press into a cylindrical bilayer tablet. Theosmotic face of the tablet is convex, to conform to the shape of thedevice, while the push plate face of the tablet is flat. Tabletting wasconducted to produce a clean, distinct interface between the two layers.

The vessel portion (first housing) of the device, with one closed andone open end, is composed of polyethylene and is prepared by placing thepolyethylene in an extruder with a barrel temperature of 130° C. andextruding the material into a mold for the vessel. The polyethylene isallowed to cool in the mold, after which the finished vessel is removed.An exit orifice is drilled through the closed end of the vessel.

To prepare the cap portion (second housing) of the device, 70 wt %cellulose acetate 320 and 30 wt % polypropylene glycol are thoroughlymixed together and the mixture is added to the hopper of a screwextruder. The polymeric mixture is heated at 127° C. as it is extrudedthrough the heated barrel of the extruder and is extruded into a moldfor the cap. The polymer mixture is allowed to cool after injection intothe mold, after which the cap is removed.

The fluid-passage means is formed as a screen with fine openings and iscomposed of the same polymeric material as the vessel portion. Afterheating, the polyethylene is molded into a disk shape (with an outsidediameter equal to the inside diameter of the vessel at its open end)with fine openings extending through it. Alternatively, thefluid-passage means is formed as a macroporous plug made by sinteringtogether polymeric particles of high density polyethylene orpolypropylene (marketed as Porex®), the plug having an outside diameterequal to the inside diameter of the vessel at its open end.

To assemble the delivery device, a first osmotic engine bilayer tabletis placed into the vessel, with the partition layer portion of thetablet facing into the vessel. A fluid-passage screen or plug is thenplaced into the vessel, flush with the bilayer tablet and also flushwith the open end of the vessel. The screen or plug is secured in placeby ultrasound welding. The vessel is then turned over and the desiredactive agent formulation is placed into the vessel through the exitorifice by manual or automated fill mechanisms. The exit orifice is thensealed with a wax having a melting point of about 34° C., by dipping theexit end of the vessel in the melted wax and allowing it to cool forabout 20 seconds, after which the excess wax is wiped off. Next, asecond osmotic engine bilayer tablet is placed into a completed cap,with the convex osmotic layer pointed into the closed end of the cap andthe push plate exposed toward the cap opening. The open end of thefilled vessel is fitted inside the open end of the cap, and the twopieces are compressed together until cap, second osmotic bilayer tabletand vessel fit together tightly. When the delivery device is placed inan environment at 37° C. (e.g., the body temperature of a human), thewax sealing the exit orifice is melted away to allow delivery of activeagent.

EXAMPLE 2

Another embodiment of a delivery device according to the presentinvention is prepared as follows.

A first osmotic engine portion is prepared as described in Example 1.

A second osmotic engine portion is prepared substantially as describedin Example 1, except that the second osmotic portion does not include apush plate but comprises only 150 mg of the polymeric osmoticformulation pressed into a monolayer tablet having a convex face and aflat face.

The vessel portion (first housing) of the device, composed of lopolyethylene, is extruded following the procedures of Example 1 into amold. The resulting vessel has one open and one closed end, the closedend being flat and having a plurality of openings molded into it to formthe screen portion of the fluid-passage means.

The semipermeable membrane portion of the fluid-passage means is formedas a semipermeable membrane and is composed of the same polymericmaterial as the first cap portion, below. After heating, the polymericmixture is extruded as a sheet and, after cooling of the sheet, a circleor disk having the same diameter as the inside diameter of the vesselportion at its closed end is punched out of the sheet to make thesemipermeable membrane disk.

The first cap portion (second housing) of the device is prepared bymelt-blending together 60 wt % ethylene vinyl acetate (with 9% vinylacetate content) and 40 wt % polyvinyl pyrrolidone at 110° C. andinjection-molding or extruding the mixture into a mold for the cap. Thepolymer mixture is allowed to cool after injection, after which the capis removed from the mold.

The second cap portion is made by extruding ethylene vinyl acetate (9%vinyl acetate content) into a mold for a cap to fit over the open end ofthe vessel portion. After the finished second cap is removed from themold, an exit orifice is drilled through the cap.

To assemble the delivery device, the semipermeable membrane disk isplaced into the vessel through its open end and situated against itsclosed end. The first osmotic engine bilayer tablet is placed into thevessel, with the osmotic layer portion of the tablet in contact with thesemipermeable membrane. The desired active agent formulation is thenplaced into the vessel by manual or automated fill mechanisms. Thevessel is then closed by placing the second cap with the exit orificeover the open end of the vessel. The cap is secured in place by adhesiveseal. Next, the second osmotic engine monolayer tablet is placed into acompleted first cap, with the convex face of the tablet pointed into theclosed end of the cap. The flat, screen end of the vessel is fittedinside the open end of the first cap, and the two pieces are compressedtogether until cap, second osmotic layer and vessel fit togethertightly.

EXAMPLE 3

A further embodiment of the delivery device of the present invention isprepared following the procedures of Example 2, except that the secondcap portion is comprised of gelatin, which will erode when placed in afluid environment. No exit orifice is drilled in this second cap. Theactive agent formulation is comprised of a plurality of individualtablets which are placed longitudinally within the vessel portion. Theactive agent tablets are separated by non-active agent-containing layershaving the same composition as the partition layer.

The above description has been given for ease of understanding only. Nounnecessary limitations should be understood therefrom, as modificationswill be obvious to those skilled in the art.

What is claimed is:
 1. A fluid-imbibing delivery device for dispensingan active agent to a fluid environment of use over a predeterminedprolonged period of time of from about 1 hour to about 48 hours after aninitial, preset delayed startup of delivery, which device maintains itsintegrity in the fluid environment, wherein the device comprises:(a) afirst housing and a second housing, the first and second housings beingin reversibly sliding telescoping arrangement with each other, the firsthousing being impermeable in at least a portion and having an endadapted to fit within the second housing and the second housing beingsemipermeable in at least a portion; (b) an active agent deliverychamber within the first housing comprising(i) at least one active agentformulation, (ii) a first fluid-activated expansion means selected fromosmagents, osmopolymers or mixtures of osmagents with osmopolymers forexpelling the active agent formulation from the delivery device, (iii)an exit means, and (iv) a fluid-passage means selected from the groupconsisting of a screen, a microporous membrane, a semipermeablecomposition and combinations of these; and (c) an expansion chamberwithin the second housing, the expansion chamber comprising(i) a secondfluid-activated expansion means selected from osmagents, osmopolymers ormixtures of osmagents with osmopolymers for separating apart the firstand second housings, and (ii) a push plate adjacent the telescoping endof the first housing.
 2. A delivery device according to claim 1 whichfurther comprises a partition layer between the active agent formulationand the first expansion means.
 3. A delivery device according to claim 1wherein the first housing is comprised of an impermeable material andthe second housing is comprised of a semipermeable material.
 4. Adelivery device according to claim 1 wherein the active agentformulation is a liquid, a solid, a semi-solid, a thermoresponsivecomposition or a plurality of dosage forms.
 5. A method for deliveringan active agent to a fluid environment of use for a predeterminedprolonged period of time of from about 1 hour to about 48 hours after aninitial delayed startup of delivery, the method comprising:(1) placing afluid-imbibing delivery device into the fluid environment, which devicemaintains its integrity in the fluid environment, wherein the deliverydevice comprises:(a) a first housing and a second housing, the first andsecond housings being in reversibly sliding telescoping arrangement witheach other, the first housing being impermeable in at least a portionand having an end adapted to fit within the second housing and thesecond housing being semipermeable in at least a portion; (b) an activeagent delivery chamber within the first housing comprising(i) at leastone active agent formulation, (ii) a first fluid-activated expansionmeans selected from osmagents, osmopolymers or mixtures of osmagentswith osmopolymers for expelling the active agent formulation from thedelivery device, (iii) an exit means, and (iv) a fluid-passage meansselected from the group consisting of a screen, a microporous membrane,a semipermeable composition and combinations of these; and (c) anexpansion chamber within the second housing, the expansion chambercomprising(i) a second fluid-activated expansion means selected fromosmagents, osmopolymers or mixtures of osmagents with osmopolymers forseparating apart the first and second housings, and (ii) a push plateadjacent the telescoping end of the first housing; (2) allowing fluid tobe imbibed through at least a portion of the second housing of thedelivery device for causing the second expansion means to expand andexert pressure on the slidably connected first and second housings topush apart and separate the two housings to expose the fluid-passagemeans to the environment; and (3) allowing fluid to be imbibed throughthe fluid-passage means for causing the first expansion means to expandto push the active agent formulation from the delivery device.
 6. Amethod according to claim 5 wherein the delivery device furthercomprises a partition layer between the active agent formulation and thefirst expansion means.
 7. A method according to claim 5 wherein thefirst housing is comprised of an impermeable material and the secondhousing is comprised of a semipermeable composition.
 8. A methodaccording to claim 5 wherein the active agent formulation is a liquid, asolid, a semisolid, a thermoresponsive composition or a plurality ofdosage forms.
 9. A fluid-imbibing delivery device for dispensing anactive agent in a pulsatile manner to a fluid environment of use over apredetermined prolonged period of time of from about 1 hour to about 48hours after an initial, preset delayed startup of delivery, which devicemaintains its integrity in the fluid environment, wherein the devicecomprises:(a) a first housing and a second housing, the first and secondhousings being in reversibly sliding telescoping arrangement with eachother, the first housing being impermeable in at least a portion andhaving an end adapted to fit within the second housing and the secondhousing being semipermeable in at least a portion; (b) an active agentdelivery chamber within the first housing comprising(i) a plurality ofactive agent layers containing at least one active agent longitudinallydisposed with the active agent delivery chamber, the active agent layersbeing separated by non-active agent-containing layers, (ii) a firstfluid-activated expansion means selected from osmagents, osmopolymers ormixtures of osmagents with osmopolymers for expelling the active agentlayers from the delivery device, (iii) an exit means, and (iv) afluid-passage means selected from the group consisting of a screen, amicroporous membrane, a semipermeable composition and combinations ofthese; and (c) an expansion chamber within the second housing, theexpansion chamber comprising(i) a second fluid-activated expansion meansselected from osmagents, osmopolymers of mixtures of osmagents withosmopolymers for separating apart the first and second housings, and(ii) a push plate adjacent the telescoping end of the first housing. 10.A delivery device according to claim 9 which further comprises apartition layer between the active agent layers and the first expansionmeans.
 11. A delivery device according to claim 9 wherein the exit meansis closed by an erodible material.
 12. A delivery device according toclaim 9 which further comprises a retaining structure across the exitmeans.
 13. A method for delivering an active agent in a pulsatile mannerto a fluid environment for use for a predetermined prolonged period oftime of from about 1 hour to about 48 hours after an initial delayedstartup of delivery, the method comprising:(1) placing a fluid-imbibingdelivery device into the fluid environment, which device maintains itsintegrity in the fluid environment, wherein the delivery devicecomprises:(a) a first housing and a second housing, the first and secondhousings being in reversibly sliding telescoping arrangement with eachother, the first housing being impermeable in at least a portion andhaving an end adapted to fit within the second housing and the secondhousing being semipermeable in at least a portion; (b) an active agentdelivery chamber within the first housing comprising(i) a plurality ofactive agent layers containing at least one active agent longitudinallydisposed with the active agent delivery chamber, the active agent layersbeing separated by non-active agent-containing layers. (ii) a firstfluid-activated expansion means selected from osmagents, osmopolymers ormixtures of osmagents with osmopolymers for expelling the active agentlayers from the delivery device, (iii) an exit means, and (iv) afluid-passage means selected from the group consisting of a screen, amicroporous membrane, a semipermeable composition and combinations ofthese; and (c) an expansion chamber within the second housing, theexpansion chamber comprising(i) a second fluid-activated expansion meansselected from osmagents, osmopolymers or mixtures of osmagents withosmopolymers for separating apart the first and second housings, and(ii) a push plate adjacent the telescoping end of the first housing; (2)allowing fluid to be imbibed through at least a portion of the secondhousing of the delivery device for causing the second expansion means toexpand and exert pressure on the slidably connected first and secondhousings to push apart and separate the two housing to expose thefluid-passage means to the environment; and (3) allowing fluid to beimbibed through the fluid-passage means for causing the first expansionmeans to expand to push the active agent layers and the non-activeagent-containing layers sequentially from the delivery device.
 14. Amethod according to claim 13 which further comprises a partition layerbetween the active agent layers and the first expansion means.
 15. Amethod according to claim 13 wherein the exit means is closed by anerodible material.
 16. A method according to claim 13 which furthercomprises a retaining structure across the exit means.